Cancer is a major public health problem in the United States and in the world. Currently, one in 4 deaths in the United States is due to cancer. Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,596,670 new cancer cases and 571,950 deaths from cancer were projected to occur in the United States in 2011. Aging of the general population and development of new forms of cancer contribute to the problem.
Attempts have been made to identify genes or other markers that would either predict response to treatment, or correlate with response to treatment. In 2009, the laboratory of Nicholas B. La Thangue published the results of a genome-wide loss of function screen that identified a role for HR23B as a sensitivity determinant for HDAC inhibitor that induced apoptosis in cells (Fotheringham et al., Cancer Cell 15:57 (2009). In a subsequent paper, the authors noted a frequent coincidence between HR23B expression and clinical response to HDAC inhibition (Khan et al., PNAS 107:6532 (2010).
Other studies described markers that correlate with sensitivity to HDAC inhibitors in cells. Shao et al. (Int. J. Cancer 127:2199(2010)) compared 4 lines that are either sensitive or resistant to panobinostat treatment and found that inhibition of BCL2 sensitized resistant lines to panobinostat treatment. BCL2 blocks the pro-apoptotic activity of BAX, and knockdown of BAX was found to diminish sensitivity to panobinostat treatment. These results were in line with previous studies showing that overexpression of BCL2 and BCL-xl blocked HDAC inhibitor mediated apoptosis (Bolden et al., Nature Reviews Drug Discovery 5:769 (2006), including apoptosis mediated by romidepsin (Peart et al., Cancer Research 63:4460 (2003). Later studies showed that romidepsin is able to induce apoptosis in lymphomas overexpressing BCL2 with delayed kinetics, but not in cells overexpressing BCL-xl (Newbold et al, Mol. Cancer Ther. 7:1066 (2008); WO/2010/047714). Peart et al. confirmed romidepsin as a substrate for P-glycoprotein (P-gp), and showed that cells overexpressing P-gp are resistant to apoptosis induced by the drug. Also Scala showed romidepsin to be a P-gp substrate (Scala et al., Molecular Pharmacology 51:1024(1997) and a substrate for Multidrug Resistance Associated Protein 1 (MRP1), but the major mechanism of acquired resistance to romidepsin in cells appears to be up-regulation of P-gp (Xiao et al., J Pharmacol and Exp Ther 313:268(2005)). In spite of the correlation between P-gp expression and romidepsin sensitivity that is observed in cell culture assays, no association exists between P-gp expression and clinical response (Bates et al., Br J Haematol 148:256 (2010).
Various laboratories have tried to establish gene expression signatures that correlate with response to treatment to HDAC inhibitors (Stimson et al., Cancer Lett 280:177 (2009)). However, these signatures vary from study to study and are most likely unique to the tumor type studied and the HDAC inhibitor used. For example, Yuka Sasakawa and colleagues tried to identify markers that predict sensitivity to romidepsin (Sasakawa et al., Biochem Pharmacol 69:603 (2005)). This study compared expression profiles of sensitive and resistant to romidepsin tumors and identified caspase 9 and MKP-1 genes as marker genes to predict sensitivity to romidpsin treatment. However, the validity of these markers is likely to be limited to these specific studies.
Between 2,000 and 3,000 new cases of cutaneous T-cell lymphoma (CTCL) occur in the United States each year, with mycosis fungoides (MF) and the Sézary syndrome (SS) being the predominant subtypes. Romidepsin activity in T-cell lymphomas was observed in phase I and II trials conducted by the National Cancer Institute (NCI) in patients with both MF and SS. (Piekarz et al., Blood 103: 4636 (2004); Sandor et al., Clin Cancer Res 8:718 (2002); Marshall et al., J Exp Ther Oncol 2:325 (2002); Piekarz et al., Blood 98:2865 (2001); Piekarz et al., J. Clinical Oncology 27 (32):5410 (2009)). Romidepsin was shown in a phase II clinical trial to have single-agent clinical activity with significant and durable responses in patients with cutaneous T-cell lymphoma (CTCL) (Piekarz et al., J Clinical Oncology 27 (32):5410 (2009)). Romidepsin has also been shown to have significant and sustainable single-agent activity and an acceptable safety profile for treatment of refractory CTCL (Whittaker et al. J Clin Oncol 28:4485-4491 (2010)).
Little is known about TSPYL5, which encodes Testis-specificY-encoded-like protein 5. It contains a nucleasome assembly protein domain (NAP-domain) that acts as histone chaperone. TSPYL5 has been shown to be involved in cell growth and resistance to radiation in A549 cells (Kim et al., Biochem and Biophys Res Comm 392:448 (2010). It is a target of epigenetic silencing in gastric cancers (Jung et al., Lab Invest 88:153(2008), and glioma (Kim et al., Cancer Res 66:7490 (2006)) and is thought to mediate some of its function by suppressing p53 activity via physical interaction with USP7 (Epping et al., Nature Cell Biol 13:102 (2011). There is no known connection between the levels of TSPYL5 and sensitivity to treatment with romidepsin or other HDAC inhibitors.
Currently, patients receiving treatment with romidepsin are not selected for treatment based on the expression of predictive markers. To improve clinical outcomes, a need exists to identify biomarkers that allow selecting cancer patients that are more likely to respond positively to HDAC inhibitor therapy while deselecting cancer patients that are likely to be resistant to HDAC inhibitor therapy.